All ETDs from UAB

Advisory Committee Chair

Hubert M Tse

Advisory Committee Members

Robinna G Lorenz

Victor M Darley-Usmar

Elena I Frolova

Chad Steele

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Type 1 diabetes (T1D) is a chronic inflammatory autoimmune disease in which autoreactive T cells selectively destroy insulin-producing pancreatic β-cells. While genetic predisposition underlies susceptibility, environmental factors are proposed to play the important role of triggering the activation of autoimmunity in T1D individuals. Viral infections, particularly by Coxsackie B viruses, are highly suspected as a precipitating event. However, the exact molecular mechanism for how viral infections elicit β-cell-specific autoimmunity remains unclear. Rodent models of virus-induced T1D suggest it is through bystander activation, during which innate antiviral responses to pancreas-tropic viral infections create an inflammatory milieu that breaks the peripheral tolerance normally keeping autoreactive T cells in check. Using the non-obese diabetic (NOD) mouse model, we have previously shown that oxidative stress and redox-regulated innate immune signaling driven by the production of NADPH oxidase 2 (NOX2)-derived superoxide is critical in T1D pathogenesis. Macrophages highly express NOX2 and are absolutely essential in T1D. Analysis of NOD macrophages lacking a functional NOX2 (NOD.Ncf1m1J) revealed that antiviral inflammatory responses to TLR3 stimulation was significantly redox-dependent. Combining these results with the proposed bystander activation model for virus-induced T1D, we hypothesized that production of NOX2-derived superoxide following Coxsackie B virus infection leads to an excessive macrophage inflammatory response that ultimately triggers T1D. Our study revealed that absence of superoxide production lead to protection against Coxsackie B3-accelerated disease, as well as continued protection against spontaneous onset. No impact on pancreatic viral load or clearance was observed. Instead, protection was preceded by dampened inflammatory TNF-α production by pancreas-infiltrating macrophages and a decreased pancreas antiviral transcriptional profile. In vitro mechanistic analyses revealed novel redox-sensitive upregulation of virus-sensing molecules. This study also revealed an early superoxide-dependent upregulation and activation of STAT1, suggesting that superoxide acts as a potent signaling molecule for establishing an inflammatory M1 macrophage phenotype. This result corroborates our study showing that NOD.Ncf1m1J macrophages throughout spontaneous T1D progression maintain an increased non-inflammatory and decreased M1 phenotype. Altogether, we provide evidence that NOX2-derived superoxide can control the antiviral response of macrophages through multiple signaling pathways, which culminates in a diabetogenic inflammatory environment following CB3 infection.



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